Stimulation of mitochondrial activity and alterations of cancer cell characteristic adenosine-5′-triphosphate (ATP) generation pathways is an anticancer strategy. (Warburg, Science 123:309-314, 1956; Zu et al., Biochem. Biophys. Res. Commun. 313:459-465, 2004; Samudio et al., Cancer Res. 69:2163-2166, 2009; Gatenby et al., Nat. Rev. Cancer 4:891-899, 2004; Kim et al., Cancer Res. 66:8927-8930, 2006; Cheong et al., Nat. Biotechnol. 30:671-678, 2012.) The molecule dichloroacetate (DCA) has the potential to become a major player in the field of cancer chemotherapy. (Bonnet et al., Cancer Cell 11:37-51, 2007; Dhar et al., Proc. Natl. Acad. Sci. USA 106:22199-22204, 2009; Sun et al., Breast Cancer Res. Treat. 120:253-260, 2010; Pearson, Nature 446:474-475, 2007.) By utilizing the metabolic switch, DCA reverses the abnormal cancer cell metabolism from aerobic glycolysis to glucose oxidation by reducing the activity of mitochondrial pyruvate dehydrogenase kinase 1 (PDK1), which negatively regulates pyruvate dehydrogenase (PDH) causing pyruvate to convert to acetyl-CoA promoting oxidative phosphorylation (Bonnet et al. 2007). DCA reduces the high mitochondrial membrane potential (Δψm) of cancer cells and increases mitochondrial reactive oxygen species (ROS) in malignant, but not in normal cells (Id.). However, therapeutically prohibitive high DCA doses are needed for suppression of tumor growth due to the lack of effective mechanisms for DCA entry into tumor cells and its localization inside the target organelle, mitochondria of cells.
One study demonstrated that extremely high concentrations of DCA are needed to induce selective tumor cell death at a concentration that has no toxic effect on normal cells (Stockwin et al., Int. J. Cancer 127:2510-2519, 2010). In physiological condition, orally or intravenously administered DCA is ionized and cannot pass through the plasma membrane by passive diffusion. Methods and compositions that allow introduction of physiologically relevant doses of DCA, as well as other therapeutics, into cancer cells are needed. Also needed are methods and compositions that allow the anionic form of DCA to cross the negatively charged inner mitochondrial membrane (IMM) to access PDK1 within the mitochondrial matrix. Such methods and compositions would be very useful in anti-cancer therapies. Moreover, such methods and compositions could be applied to other therapeutic agents besides DCA, which could also benefit from targeted delivery into the mitochondria. The compositions and methods disclosed here address these and other needs.